19-1482081-C-A
Variant names:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2
The NM_017573.5(PCSK4):c.1946G>T(p.Cys649Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00946 in 1,552,464 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.0054 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0099 ( 86 hom. )
Consequence
PCSK4
NM_017573.5 missense
NM_017573.5 missense
Scores
2
6
10
Clinical Significance
Conservation
PhyloP100: 0.832
Genes affected
PCSK4 (HGNC:8746): (proprotein convertase subtilisin/kexin type 4) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. The protease is expressed only in the testis, placenta, and ovary. It plays a critical role in fertilization, fetoplacental growth, and embryonic development and processes multiple prohormones including pro-pituitary adenylate cyclase-activating protein and pro-insulin-like growth factor II. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.010106891).
BP6
Variant 19-1482081-C-A is Benign according to our data. Variant chr19-1482081-C-A is described in ClinVar as [Benign]. Clinvar id is 2648935.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Homozygotes in GnomAdExome4 at 86 gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PCSK4 | NM_017573.5 | c.1946G>T | p.Cys649Phe | missense_variant | Exon 15 of 15 | ENST00000300954.10 | NP_060043.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00543 AC: 826AN: 152184Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00474 AC: 704AN: 148602Hom.: 4 AF XY: 0.00463 AC XY: 376AN XY: 81296
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GnomAD4 exome AF: 0.00990 AC: 13866AN: 1400162Hom.: 86 Cov.: 33 AF XY: 0.00966 AC XY: 6688AN XY: 692098
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GnomAD4 genome AF: 0.00542 AC: 826AN: 152302Hom.: 1 Cov.: 33 AF XY: 0.00475 AC XY: 354AN XY: 74458
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
May 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
PCSK4: BS1, BS2 -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at